Methods of synthesis of substituted tetrahydrofuran compound

Details Methods of synthesis of substituted tetrahydrofuran compound Methods of synthesis of substituted tetrahydrofuran compound

2001-10-02

2003-04-01

Dentz, Bernard (Department: 1625)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C549S497000

Reexamination Certificate

active

06541647

ABSTRACT:

BACKGROUND
1. Field of the Invention
The present invention provides new methods for preparation of 2-(4-fluorophenoxymethyl)-5-(4-N-hydroxyureidyl-1-butynyl)-tetrahydrofuran (“compound
1
”) and synthetic precursors thereof.
2. Background
Leukotrienes are recognized potent local mediators, playing a significant role in inflammatory and allegeric responses, including arthritis, asthma, psoriasis and thrombotic disease. Leukotrienes are produced by the oxidation of arachidonic acid by lipoxygenase. More particularly, arachidonic acid is oxidized by 5-lipooxygenase to the hydroperoxide 5-hydroperoxy-eicosatetraenoic acid (5-HPETE), that is converted to leukotriene A
4
, that in turn can be converted to leukotriene B
4
, C
4
, or D
4
. The slow-reacting substance of anaphylaxis is now known to be a mixture of leukotrienes C
4
, D
4
and E
4
, all of which are potent bronchoconstrictors.
Efforts have been made to identify receptor antagonists or inhibitors of leukotriene biosynthesis, to prevent or minimize pathogenic inflammatory responses mediated by leukotrienes.
For example, European Patent Application Nos. 901171171.0 and 901170171.0 report indole, benzofuran, and benzothiophene lipoxygenase inhibiting compounds.
Various 2,5-disubstituted tetrahydrofurans have exhibited significant biological activity, including as lipoxygenase inhibitors. See U.S. Pat. Nos. 5,703,093; 5,681,966; 5,648,486; 5,434,151; and 5,358,938.
While such compounds are highly useful therapeutic agents, current methods for synthesis of least some of the compounds require lengthy routes, and reagents and protocols that are less preferred in larger scale operations, such as to produce kilogram quantities.
SUMMARY OF THE INVENTION
We have now found new methods for preparation of 2-(4-fluorophenoxymethyl)-5-(4-N-hydroxyureidyl-1-butynyl)-tetrahydrofaran and precursor compounds thereof. 2-(4-Fluorophenoxymethyl)-5-(4-N-hydroxyureidyl-1-butynyl)-tetrahydrofuran is sometimes referred to herein as “compound
1
”. Preferred methods of the invention provide compound
1
in optically active form, particularly as an enantiomerically enriched mixture of the following stereoisomer (i.e. 2S,5S-trans-2-(4-fluorophenoxymethyl)-5-(4-N-hydroxyureidyl-1-butynyl)-tetrahydrofuran):
The methods of the invention utilize reagents and synthetic protocols that facilitate large scale manufacture, and provide increased yields relative to prior approaches.
In a first aspect of the invention, compound
1
and precursors thereof are provided by reacting 4-fluorophenol with an epoxide having a reactive C3 carbon, e.g. a glycidyl compound substituted at the C3 position with an electron-withdrawing group such as halo (e.g. epichlorohydrin, epibromohydrin), mesyl or tosyl (glycidyl mesylate and glycidyl tosylate), etc., to form an epoxyphenylether ((glycidyl-4-fluorophenyl ether) in the presence of base and preferably at or above about 0° C. The reacted epoxide can be optically active if desired. The formed epoxyphenylether is then reacted with an active methylene compound to form a lactone, preferably a &ggr;-lactone, with 5 ring members. The active methylene compound can be a variety of agents. Diethyl and dimethyl malonate are generally preferred, which provide an ethyl or methyl ester as a lactone ring substituent, i.e. 2-carboalkoxy-(4-fluoro-phenoxy-methyl)-&ggr;-butyrolactone, where the alkoxy group suitably has from 1 to about 12 carbon atoms, more preferably 1 to about 6 carbon atoms, still more preferably 1 to about 3 carbons with methoxy and ethoxy particularly preferred. That ester group is then removed (e.g. via hydrolysis and decarboxylation), and the lactone suitably reduced to a hydroxy-substituted tetrahydrofuran, specifically 4-fluorophenoxymethyl-hydroxytetrahydrofuran.
The hydroxy tetrahydrofuran is further functionalized by activating the hydroxyl substituent of the hydroxytetrahydrofuran-phenyl ether followed by substitution of the corresponding position of the tetrahydrofuran ring with by a 1-alkyne reagent. Also, rather than directly activating the hydroxyl moiety, that group can be replaced with a halide, and the halide-substituted tetrahydrofuran reacted with a benzylsulfonic acid reagent.
It also has been found that methods of the invention enable such substitution of the tetrahydrofuran to proceed with extremely high stereoselectivity, e.g. at least greater than about 60 mole percent of one stereoisomer than the other, more typically greater than about 70 or 75 mole percent of one stereoisomer than the other isomer. Recrystallization has provided very high optical purities, e.g. about 95 mole %, 97 mole % or even 99 mole % or more of the single stereoisomer.
In another aspect, methods are provided that involve cleavage of a bis-compound to provide high yields of compound
1
. These methods preferably involve condensation of mannitol with an alkanoyl particularly an aldehyde such as formaldehyde to form a trialkylene mannitol such as a tri(C
1-10
alkylene) mannitol e.g. trimethylene mannitol when using formaldehyde, which is then cleaved to form 2,5,-
O
-methylene-mannitol, which has two primary hydroxyl groups and two secondary hydroxyl groups. The primary hydroxyl groups are protected (e.g. as esters) and the secondary hydroxyl groups then are suitably cyclized, e.g. with a trialkylorthoformate reagent, to provide a cyclic ether. The protected primary alcohols are then converted to aryl ethers, followed by cleavage of the cyclic ether to provide again the secondary hydroxyl groups. The mannitol compound then undergoes oxidative cleavage to provide the corresponding alicyclic dialdehyde, which aldehyde groups are functionalized to bis-&agr;,&bgr;-unsaturated esters. The carbon-carbon double bonds of that compound are suitably saturated, and the bis-compound cleaved and the cleavage products cyclized to provide two molar equivalents of 4-fluorophenoxy-methyl-&ggr;-butyrolactone which can be further functionalized as described above.
In yet another aspect of the invention, preparative methods are provided that include multiple reactions that surprisingly proceed as a single step without isolation of intermediates to provide compound
1
.
Moreover, it has been surprisingly found that the one step procedure is enantioselective. Hence, if the starting reagent (a 2,3-epoxide) is optically active, the resulting compound
1
also will be optically active.
More particularly, in this aspect of the invention, a compound is reacted that has at least a six-carbon alkyl or alkylene chain that is activated at the 1- and 6-carbon positions such as by substitution by suitable leaving groups, and 2- and 3-carbon positions of the chain form an epoxide ring. The compound suitably has about 6-12 carbons in the chain. The leaving groups of the 1- and 6-positions may be e.g. halo, such as chloro or bromo, or an ester, such as an alkyl or aryl sulfonic ester, e.g. mesylate or other C
1-10
alkyl sulfonic ester, or a phenyl sulfonic ester such as tosylate and the like, or an arylalkyl ester such as benzylsulfonic ester. Preferably, the 1-position is halo-substituted, particularly bromo-, iodo- or chloro-substituted, and the 6-position is substituted by an ester such as by a benzylsulfonyl group. That compound is reacted with a molar excess of a strong base such as an alkyllithium reagent that affords compound
1
in a single step.
In another aspect of the invention, a chiral synthon is preferably employed such as glyceraldehyde, mannitol, ascorbic acid, and the like, to provide a stereoselective route to desired stereoisomers of compound
1
. This route includes formation of a substituted dioxolane, typically a 1,3-dioxolane (particularly (2,2-dimethyl)- 1,3-dioxolane), which preferably is optically active. A side chain of the dioxolane, preferably at the 4-position, is suitably extended e.g. by one or more Wittig reactions, typically one or two Wittig reactions that provide B-unsaturated moieties such as an &agr;,&bgr;-unsaturated alkyl ester. Such an &agr;,&bgr;-unsaturated moiety provided then can be epoxidized, preferably by asymmet

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